1. Field
The invention relates to a process useful to produce vitamin D analogs, such as calcitriol, sold under the brand name Rocaltrol(copyright).
2. Description
Processes for manufacturing vitamin D analogs typically require multiple steps and chromatographic purification. See, Norman, A. W.; Okamura, W. H. PCT Int. Appl. WO 9916452 A1 990408; Chem Abstr. 130:282223. Batcho, A. D.; Bryce, G. F.; Hennessy, B. M.; Iacobelli, J. A.; Uskokovic, M. R. Eur. Pat. Appl. EP 808833, 1997; Chem. Abstr. 128:48406. Nestor, J. J.; Manchand, P. S.; Uskokovic, M. R. Vickery, B. H. U.S. Pat. No. 5,872,113, 1997; Chem. Abstr. 130:168545. The present invention seeks to provide an efficient synthesis of the A-ring portion of such vitamin D analogs.
The subject invention provides a method of stereospecifically producing a compound of formula: 
or its enantiomer 
wherein R1 is C1-C6 alkyl and R2 is a hydroxy protective group, which comprises reacting a compound of formula: 
or its enantiomer, respectively, 
wherein R1 and R2 are as above and the stereochemistry of both the compound of formula 1AA and the compound of formula 2AA is the same at carbons 1 and 3, respectively, and the stereochemistry of both the compound of formula 1AA* and the compound of formula 2AA* is the same at carbons 1 and 3, respectively, with a fluorinated alcohol having a pKa lower than about 9, in the presence of a palladium catalyst to yield the compound of formula 2AA or 2AA*, respectively.
The palladium catalyst is typically a palladium-phosphine catalyst, such as palladium-triarylphosphine. Preferred palladium-triarylphosphine catalysts are selected from the group consisting of palladium-triphenylphosphine, palladiumtris(2-methoxyphenyl)phosphine, palladium-tris(3-methoxyphenyl)phosphine, palladium-tris(4-methoxyphenyl)phosphine, palladium-tris(o-tolyl)phosphine, palladium-tris(m-tolyl)phosphine, palladium-tris(p-tolyl)phosphine, palladium-tris(4-fluorophenyl)phosphine, palladium-tris(p-trifluoromethylphenyl)phosphine, and palladium-tris(2-furyl)phosphine. Another palladium catalyst is palladium-1,2-bis(diphenylphosphino) ethane.
The fluorinated alcohol is favorably selected from the group consisting of: 
wherein X is phenyl or CF3. Of these fluorinated alcohols, the compounds 
Novel intermediates provided by the subject invention include a compound having the structure: 
wherein R1 is C1-C6 alkyl; or preferably a compound of the structure: 
These intermediates and the compounds that follow, as well as their enantiomers, form a portion of the subject application.
Another novel intermediate is a compound having the structure: 
wherein R1 is C1-C6 alkyl and R2 is a hydroxy protective group selected from the group consisting of trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyidimethylsilyl (xe2x80x9cTBSxe2x80x9d), dimethylthexylsilyl, triphenylsilyl, and t-butyidiphenylsilyl. Preferably, this compound has the structure: 
wherein R1 is C1-C6 alkyl, or the structure: 
wherein R2 is a hydroxy protective group selected from the group consisting of trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl, dimethylthexylsilyl, triphenylsilyl, and t-butyldiphenylsilyl; or a compound of the structure: 
Yet another novel intermediate is the compound having the structure: 
wherein R1 is C1-C6 alkyl and R2 is a hydroxy protective group selected from the group consisting of trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl, dimethylthexylsilyl, triphenylsilyl, and t-butyldiphenylsilyl; or the compound having the structure: 
wherein R1 is C1-C6 alkyl; or the compound having the structure: 
wherein R2 is a hydroxy protective group selected from the group consisting of trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl, dimethylthexylsilyi, triphenylsilyl, and t-butyldiphenylsilyl; or the compound having the structure: 
Other novel intermediates include a compound having the structure: 
wherein R1 is C1-C6 alkyl; or the compound having the structure: 
The novel intermediate having the structure: 
wherein R1 is C1-C6 alkyl; and the compound having the structure: 
are also provided. Other intermediates include the compound having the structure: 
wherein R1 is C1-C6 alkyl; and the compound having the structure: 
The subject invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention but are not to be construed as limiting.
The subject invention is concerned generally with a stereospecific and regioselective process for converting compounds of formula 1 to compounds of formula 2. However, as explained below, there are certain differences between the processes involving compounds of formula 1 wherein the substituents at the 1 and 3 carbons are attached cis-, i.e. on the same side of the plane of the six-membered ring, and compounds of formula 1 wherein the substituents at the 1 and 3 carbons are attached trans-, i.e. on opposite sides of the plane of the six-membered ring. 
The process results in the compound of formula 2 having the same relative and absolute stereochemistry at both carbon 1 and carbon 3 as that in the compound of formula 1. Thus, if carbon 1 is in the R-configuration in the compound of formula 1, then carbon 1 will be in the R-configuration in the compound of resulting formula 2. In the above process, R1 is C1-C6 alkyl that can be straight-chain or branched. For example, methyl, ethyl, propyl, isopropyl, butyl (primary, secondary or tertiary), pentyl (primary, secondary or tertiary), or hexyl (primary, secondary or tertiary). R2 is a hydroxy protective group. The choice of protective group is readily determinable by the skilled artisan. However, a silyl protective group, such as tert-butyldimethylsilyl (xe2x80x9cTBSxe2x80x9d) is preferred.
The bonds forming the epoxide ring may be above the plane or below the plane of the molecule. When the epoxide ring is below the plane, the adjacent methyl group is above the plane. Likewise, when the epoxide ring is above the plane, the adjacent methyl is below the plane.
For example, when the substituents at carbons 1 and 3 are cis, the following situations can occur: 
When the substituents at carbons 1 and 3 are trans, the following situations can occur: 
Compounds of formula 2A-D are useful for the preparation of Vitamin D analogs, for example, for compound 2A, see: Shiuey, S. J.; Kulesha, I.; Baggiolini, E. G.; Uskokovic, M. R. J. Org. Chem. 1990, 55, 243; for compound 2B, see: Nagasawa, K.; Zako, Y.; Ishihara, H.; Shimizu, I. Tetrahedron Lett 1991, 32, 4937. Nagasawa, K.; Zako, Y.; Ishihara, H.; Shimizu, I. J. Org. Chem. 1993, 58, 2523; for compound 2C, see: Hatakeyama, S.; Iwabuchi, Y. PCT lnt. Appl. WO 9915499 A1 990401; Chem. Abstr. 130:252533; and. for compound 2D, see: Shimizu, N. Jpn. Kokai Tokkyo Koho JP 04305553 A2 921028; Chem. Abstr 118:191249. Shimizu, N. Jpn. Kokai Tokkyo Koho JP 04305548 A2 921028; Chem. Abstr. 118:212477. Minojima, T.; Tomimori, K.; Kato, Y. Jpn. Kokai Tokkyo Koho JP 02286647 A2 901126; Chem. Abstr. 114:184872.
Compounds of formula 1A and 1C are enantiomers, and can be prepared from known compounds. For example, the starting material may be (+)-Carvone for the preparation of 1A, and the starting material may be (xe2x88x92)-Carvone for the preparation of 1C [Liu, H. J.; Zhu, B. Y. Can. J. Chem. 1991, 69, 2008]. The compound of formula 3 or its enantiomer may be obtained by reacting (+)-carvone or (xe2x88x92)-carvone, respectively, with an acetic acid ester, such as methylacetate, ethylacetate, propylacetate, isopropylacetate, t-butyl, iso-butyl, or sec-butyl acetate, pentyl (primary, seconadry or tertiary) acetate, or hexyl (primary, seconadry or tertiary) acetate, according to procedures set forth in the above publication. A skilled chemist having read the present specification would know how to produce a given enantiomer by choosing the corresponding enantiomeric starting material. 
In the compounds of the above scheme, R1 is C1-C6 alkyl that can be straight-chain or branched. For example, methyl, ethyl, propyl, isopropyl, butyl (primary, secondary or tertiary), pentyl (primary, secondary or tertiary), or hexyl (primary, secondary or tertiary). R2 is a hydroxy protective group, for example a silyl protective group. The choice of hydroxy protective group is readily apparent to the skilled artisan, see for example T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd Ed., John Wiley and Sons, 1991. Acceptable hydroxy protective groups for use in connection with the subject invention include silyl ethers such as trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl, dimethylthexylsilyl, triphenylsilyl, and t-butyldiphenylsilyl.
Step A of the above process is the highly regio- and stereoselective epoxidation of the known [Liu, H. J.; Zhu, B. Y. Can. J. Chem. 1991, 69, 2008] allyl alcohol of formula 3 catalyzed by vanadyl acetylacetonate to obtain the epoxide of formula 4. The side chain double bond is then ozonized to give the ketone of formula 5. A Baeyer-Villiger oxidation of the ketone of formula 5, followed by hydrolysis of the resulting acetate 6 gave alcohol 7. Selective silylation of the secondary alcohol and dehydration of the tertiary alcohol gave unsaturated ester of formula 1A in the (E) configuration.
Step A
The allyl alcohol of formula 3 can be epoxidized in methylene chloride using a catalytic amount of vanadyl acetylacetonate and a nonane solution of tert-butyl hydroperoxide in the presence of molecular sieves. Alternatively, the reaction can be carried out in refluxing cyclohexane with constant removal of water by a Dean-Stark condenser, using 1.5 mol % of the vanadium complex and about 1.2 equiv. of the hydroperoxide to give a complete reaction after five hours and product in a good yield. The epoxide of formula 4 tends to be unstable. Accordingly, it is advisable to quench the excess hydroperoxide with sodium bisulfite, wash the reaction mixture several times with saturated sodium bicarbonate solution, concentrate it at 30xc2x0 C. under reduced pressure, and dried it at room temperature under high vacuum. The resulting mixture of the crude product and nonane (from the hydroperoxide solution) can then be subjected to ozonolysis in step B.
Step B
A methanolic solution containing the epoxide of formula 4 can be ozonized in the presence of sodium bicarbonate, with dry ice-acetone cooling. A Polymetrics Laboratory Ozonator Model T-816 (Polymetrics, Inc.) can be used to generate the ozonized air (shell pressure 6 PSIG; flow rate 4 LPM; 110 V). This is followed with a reduction with dimethyl sulfide to obtain the ketone of formula 5. Sodium bicarbonate should be removed by filtration prior to concentration below 30xc2x0 C.
Step C
The compound of formula 5 can be oxidized under modified Baeyer-Villiger oxidation conditions (excess meta-chloroperbenzoic acid in the absence of base) in a mixure of hexane and ethyl acetate. Greater amounts of hexane in the mixture accelerate the reaction. However, a too high ratio of hexane to ethyl acetate causes an additional layer in the reaction mixture and the production of by-products. A 3:1 mixture of hexane to ethyl acetate was found particularly suitable.
Step D
The acetate of formula 6 can be hydrolyzed in methanol with a catalytic amount of sodium methoxide (15 mol %) with ice-water cooling. The product of formula 7 can then be crystallized from ethyl acetate-hexane and isolated.
Step E
Selective protection of the secondary alcohol over the tertiary alcohol in formula 7 can be achieved using known protection technology, such as t-butyldimethylsilyl chloride and imidazole in tetrahydrofuran. Other silyl protective groups, such as trimethylsilyl, triethylsilyl, tripropylsily, triisopropylsilyl, dimethylthexylsilyl, triphenylsilyl, and t-butyldiphenylsilyl protective groups can be similarly used, when a corresponding silylchloride is reacted with the compound of formula 7 in the presence of base, such as imidazole, pyridine, or other aromatic or aliphatic tertiary amine. Imidazole hydrochloride that precipitates from the reaction mixture can be removed by filtration. The filtrate can be concentrated and then introduced to the next step without further purification. Alternatively, silylation may be performed in pyridine and the reaction mixture can then be added directly to the dehydration mixture (i.e., pyridine/thionyl chloride) in Step F.
Step F
The protected (for example silyl) ether of formula 8 can be dehydrated to give the compound of formula 1A on treatment with thionyl chloride in pyridine. Adding a THF solution of the compound of formula 8 into a preformed, cold thionyl chloride/pyridine mixture minimizes formation of by-product. The product can be used in the next step without purification. Although this crude product may contain protective group (for example silyl) by-products, the protective group should be stable under these dehydration conditions.
Compounds of formula 1B and 1D are enantiomers, and can be prepared from known compounds. For example, the starting material may be (+)-Carvone [Okamura, W. H.; Aurrecoechea, J. M.; Gibbs, R. A.; Norman, A. W. J. Org. Chem. 1989, 54, 4072] for the preparation of 1B, and the starting material may be (xe2x88x92)-Carvone [Jones, Joel, Jr.; Kover, W. B. Synth. Commun. 1995, 25, 3907] for the praparation of 1D. Thus, compound 9 or its enantiomer may be obtained from (+)-Carvone or (xe2x88x92)-Carvone, respectively, by diastereoselective epoxidation according to procedures set forth in the above publications. A skilled chemist having read the present specification would know how to produce a given enantiomer by choosing the corresponding enantiomeric starting material. 
Step G
The compound of formula 9 is known [Klein, E.; Ohloff, G. Tetrahedron 1963, 19, 1091. Okamura, W. H.; Aurrecoechea, J. M.; Gibbs, R. A.; Norman, A. W. J. Org. Chem. 1989, 54, 40723].
At low temperature (xe2x88x9270xc2x0 C.) a 1,3-dipolar cycloaddition of ozone to the compound of formula 9 occurs to give an ozonide, which at a higher temperature (e.g., room temperature) releases formaldehyde via a retro-1,3-dipolar cycloaddition to form carbonyl oxide. In the presence of methanol as a co-solvent, the carbonyl oxide is efficiently trapped by the alcohol to give the desired hydroperoxide of formula 10A (Step G1) which is then acylated to the compound of formula 10B (Step G2). Variations on common acylation are readily apparent to one of ordinary skill of the art. In the compound of formula 10B, R3 can be C1-C6 alkyl, phenyl, 4-nitrophenyl, or CF3. Such variations are readily made by the skilled artisan.
Excess methanol may interfere with this acylation. However, a clean reaction can be achieved with 4 equivalents of methanol. Then, the hydroperoxide can be acetylated in situ with 7 equivalents of acetic anhydride and triethylamine in the presence of a catalytic amount of DMAP atxe2x88x925xc2x0 C. to obtain peroxyacetate 10B, where R is a methyl group. Other acylating agents may be similarly used and the resulting peroxyester subjected to the Criegee rearrangement as described below. Such apropriate acylating agents are aliphatic and aromatic acid halides (chlorides or bromides) and acid anhydrides, such as acetylchloride, acetic anhydride, propionylchloride, benzoylchloride, 4-nitrobenzoylchloride, and trifluoroacetic anhydride. These acylating agents may react with hydroperoxide 10A in the presence of base such as triethylamine, as above, to give the corresponding peroxyesters 10B, where R is methyl, ethyl, phenyl, 4-nitrophenyl, trifluoromethyl. However, a peroxyacetate 10B where R is methyl, is preferred.
Step H1
The peroxyester of formula 10B is immediately subjected to the Criegee rearangement to yield the alcohol of formula 11, preferably in methanol. The peroxyacetate of formula 10B tends to be unstable. Accordingly, sodium acetate may be added to prevent acid-catalyzed solvolysis of the compound of formula 10 to the corresponding dimethyl acetal and Step H1 preferably follows Step G immediately. An aqueous workup of the reaction mixture should be used to remove acidic and basic by-products in order to obtain purified compound of formula 11.
Step H2
After solvent exchange with acetonitrile, the product of formula 11 can be protected (for example, silylated) to give the ketone of formula 12. The relatively volatile protective group (for example, silyl) by-products can be removed at 45xc2x0 C. under high vacuum and the crude product of formula 12 obtained.
Protection of the secondary alcohol in formula 11 can be achieved using known protection technology, for example using t-butyldimethylsilyl chloride and imidazole. Other silyl protective groups, such as trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, dimethylthexylsilyl, triphenylsilyl, and t-butyldiphenylsilyl protective groups can be similarly used, when a corresponding silylchloride is reacted with 7 in the presence of base, such as imidazole, pyridine, or other aromatic or aliphatic tertiary amine under controlled conditions to minimize elimination of the silyloxy group.
It is noteworthy that the product of the Criegee rearrangement in methanol is the alcohol of formula 11 and that the corresponding acetate ester has never been observed in the course of the reaction. This contrasts to the typical Criegee rearrangement procedure (one-pot acetylation and rearrangement in dichloromethane: Schreiber, S. L.; Liew, W. F. Tetrahedron Lett 1983, 24, 2363), where an acetate is usually obtained as the major product together with a smaller amount of the corresponding alcohol. Subsequent hydrolysis of the acetate to the alcohol is problematic due to elimination of the acetoxy group.
Step I
A Wittig-Horner reaction of the compound of formula 12 can be carried out using 2.2 equiv. of tri-R1 phosphonoacetate (where R1 is a C1-C6 alkyl that can be straight-chain or branched) and 1.8 equiv. of lithium hydride in a relatively small amount of THF, at a relatively low temperature (11xc2x0 C.), for a longer reaction time (20 h) to minimize elimination of the protecting (for example,-silyloxy) group. The desired compound of formula 1B is thus obtained in approximately a 7-9:1 mixture with its Z-isomer (the compound of formula 1*B).
To illustrate the inventive aspects of the subject reaction, the reaction will be discussed with reference to the reaction of a species of formula 1A (formula 1Axe2x80x2) to form the corresponding species of formula 2A (formula 2Axe2x80x2). The same principles hold true with its enantiomerxe2x80x94compound 1C, as well as the reactions of compound 1B to form 2B, and of its enantiomerxe2x80x94compound 1D to form 2D. 
The above reaction, when using a palladium(0) triphenylphosphine catalyst [Suzuki, M.; Oda, Y.; Noyori, R. J. Am. Chem. Soc. 1979, 101, 1623] in THF at 65xc2x0 C., results in the isomerization of epoxide 1Axe2x80x2 to yield a mixture of the desired allyl alcohol of formula 2Axe2x80x2 and isomeric enone of formula 13 in a ratio of 1:3 (HPLC area% at 220 nm). It has been discovered that phosphine ligands [for example, triarylphosphines, such as triphenylphosphine, tris(2-methoxyphenyl)phosphine, tris(3-methoxyphenyl)phosphine, tris(4-methoxyphenyl)phosphine, tris(o-tolyl)phosphine, tris(m-tolyl)phosphine, tris(p-tolyl)phosphine, tris(4-fluorophenyl)phosphine, tris(p-trifluoromethylphenyl)phosphine, and tris(2-furyl)phosphine, and aryl phosphines such as 1,2-bis(diphenylphosphino)ethane] in combination with palladium(0) catalyze the isomerization and that adding a fluorinated alcohol [for example 1,1,1,3,3,3-hexafluoro-2-phenyl-2-propanol and 1,3-bis(1,1,1,3,3,3,-hexafluoro-2-hydroxypropyl)benzene, perfluoro-t-butanol] increases the yield of the desired allyl alcohol of formula 2Axe2x80x2 versus the undesired ketone of formula 13 and also improves catalyst turnover for the palladium-triphenylphosphine catalyst. The palladium-phosphine catalyst can be prepared in situ prior to the reaction from commercial palladium sources, such as Pd2dba3(CHCl3) (xe2x80x9cdbaxe2x80x9d stands for dibenzylideneacetone), and an excess (typically 4-5 equivalents) of the corresponding phosphine ligand, such as triphenylphosphine. Other palladium sources may be used as well, such as palladium(0) complexes Pd2dba3, Pddba2, and palladium(II) salts Pd(OAc)2, PdCl2, [allylPdCl]2, and Pd(acac)2 (xe2x80x9cacacxe2x80x9d stands for acetylacetonate). Alternatively, a palladium(0)-phosphine catalyst, such as tetrakis(triphenylphosphine)palladium(0), may be separately prepared and used in the reaction. However, generation of the catalyst in situ from Pd2dba3(CHCl3) and phosphine is preferred. With 1 mol % of the palladium-triphenylphosphine catalyst even a catalytic amount of the appropriate fluorinated alcohol was sufficient to increase the selectivity for allyl alcohol of formula 2Axe2x80x2 to 10:1. Increasing the amount of fluorinated alcohol of formula 15c further to 50 mol % and 100 mol % gave a 16:1 and 19:1 ratio of allyl alcohol of formula 2Axe2x80x2 to isomeric enone of formula 13, respectively. 
where X is CH3 (formula 15a), H (formula 15b), phenyl (formula 15c), or CF3 (formula 15d).
It has been discovered that selectivity correlated to the pKa of the fluorinated alcohols. Fluorinated alcohols with pKa  less than 9 were particularly effective. As shown in Table 1, a sharp increase in selectivity for the desired allyl alcohol of formula 2Axe2x80x2 occurs when the pKa of the additive dropped from 9.3 to below 8.8, suggesting a divergent reaction pathway involving protonation of an intermediate of comparable basicity. Other proton sources, such as methanol, phenols and carboxylic acids, result in no or incomplete reaction, presumably due to destruction of the catalyst.
Although the most acidic perfluoro-tert-butanol (formula 15d) gave a better selectivity (ratio of allyl alcohol of formula 2Axe2x80x2 to isomeric enone of formula 13=95:5) than the less acidic fluorinated alcohols of formulas 15c and 16, the reactions run with the alcohols of formulas 15c and 16 were cleaner than those with 15d. Using the fluorinated alcohol of formula 16, better results (ratio of allyl alcohol of formula 2Axe2x80x2 to isomeric enone of formula 13 greater than 99:1) were obtained by carrying out the reaction with 1 mol % of the palladium catalyst [prepared in situ from 0.5 mol % of Pd2dba3(CHCl3) and 5 mol % of triphenylphosphine] and 2 mol % of the alcohol of formula 16 in a less polar solvent, toluene, at the lower temperature of 35xc2x0 C. This lower reaction temperature also increased the purity of the product.
The 7:1 mixture of the compound of formula 1Bxe2x80x2 (formula 1Bxe2x80x2 is the formula 1B wherein R1 is t-Bu and R2 is TBS) and the compound of formula 1*Bxe2x80x2 (the Z-isomer of the compound of formula 1Bxe2x80x2) was subjected to the palladium catalyzed isomerization reaction as described above to yield a 88:12 mixture of the desired allylic alcohol of formula 2Bxe2x80x2 (formula 2Bxe2x80x2 is the formula 2B wherein R1 is t-Bu and R2 is TBS) and its corresponding ketone (see the following Table). Thus, the regioselectivity depends on the stereochemistry of the diene oxide double bond. Isomers 1B (E-isomer) and 1*B (Z-isomer) can be separated by chromatography. From pure E-isomers 1B the desired allylic alcohols (2Bxe2x80x2 and 2Bxe2x80x3) were obtained with high selectivity ( greater than 99%). On the other hand, (Z)-diene oxides 1*B gave ketones 13 and 14 selectively (see the table below). Both ethyl and t-butyl esters gave similar results.
Although a high selectivity ( greater than 99%) was achieved with the pure E-isomers of formula 1B, under commercial conditions it may not be practical to separate the E-isomers 1B from the Z-isomers 1*B. Thus, in practice a mixture of E/Z-isomers will typically be subjected to the epoxide opening and, after solvent exchange with DMF, the resulting mixture of allylic alcohol 2Bxe2x80x2/2Bxe2x80x3 and ketone 14/13 will be subjected to silylation. Silylation is typically achieved using t-butyldimethylsilyl chloride and imidazole using known protection technology. Other silyl protective groups, such as trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, dimethylthexylsilyl, triphenylsilyl, and t-butyldiphenylsilyl protective groups can be similarly used, when a corresponding silylchloride is reacted with alcohol 2B. Since alcohol 2Bxe2x80x2/2Bxe2x80x3 is converted to a non-polar product by silylation, while the polar ketone remains unchanged, pure silylated product can be easily isolated by a simple silica gel filtration.